SARS-CoV-2 variants have emerged independently in several countries, and research published over the past week indicates that the virus is changing more quickly than was once believed — and that it may continue to develop towards evading currently available vaccines. We deconstruct the science, summarise the breaking research, evaluate the concerns, and suggest a prescription for India.
Why do viruses mutate?
Like all life, viruses carry a genetic code in the form of nucleic acids — either DNA or RNA. When cells multiply, the DNA within them replicates as well, to make copies for the new cells. During replication, random errors are introduced into the new DNA, much like spelling errors when we write. Just as we can spell-check, our cells carry enzymes to ‘proofread’ and correct these mistakes to maintain the fidelity of our genetic material.
While the errors in DNA virus genomes can be corrected by the error-correcting function of cells in which they replicate, there are no enzymes in cells to correct RNA errors. Therefore, RNA viruses accumulate more genetic changes (mutations) than DNA viruses.
Evolution requires not just mutations, but also selection. While most mutations are deleterious to the virus, if some allow a selective advantage — say better infectivity, transmission, or escape from immunity — then the new viruses out-compete the older ones in a population. The mutations can be synonymous (silent) or non-synonymous (non-silent); the latter also changes an amino acid (protein building block) at that position in the coded protein.
How much has SARS-CoV2 mutated?
Coronaviruses have an RNA genome with two unique features. At 30,000 nucleotides (nucleic acid units) they have the largest genome among RNA viruses. This allows coronaviruses to produce an enzyme that can correct RNA replication errors. Consequently, coronaviruses have rather stable genomes, changing about a thousand times slower than influenza viruses, which too are RNA viruses that cause respiratory illness. In a January 21, 2021 preprint on bioRxiv, researchers from ACTREC, Navi Mumbai, analysed over 200,000 SARS-CoV-2 genomes to find 6.6 non-silent and 5 silent mutations per sample. They found 13 mutations hotspots that change in at least 40,000 or more samples. From 3,361 Indian Covid-19 patient samples, the researchers found comparable rates of 5.2 non-silent and 4.4 silent mutations per sample.
A mutation called D614G emerged in late January 2020 to change the amino acid at position 614 in the virus’ Spike protein from aspartate (D) to glycine (G). Because this variant infected and replicated better and produced ‘fitter’ viruses, it now accounts for over 99 per cent of the virus circulating globally. Other mutations are now emerging in this background.
Viruses with mutations within the receptor-binding domain (RBD) of the Spike protein have the most potential to evade antibodies that develop as a result of natural infection or vaccination. The RBD binds the cellular receptor allowing the virus to infect cells, and anti-RBD antibodies neutralise the virus. Such mutations were recently found in variant viruses that emerged in the UK, South Africa and Brazil.
As of January 26, about 29,000 infections are attributed to UK variants from 63 countries, many due to local transmission. These viruses carry 17 non-silent mutations, eight in the Spike protein.
Shahid Jameel is currently director of Trivedi School of Biosciences at Ashoka University. He has previously worked with the Delhi-based International Centre for Genetic Engineering and Biotechnology (ICGEB), and served as chief executive of the Wellcome Trust/DBT Alliance which funds health research. Virander Singh Chauhan is a former director of ICGEB. He is best known for his efforts towards developing a vaccine for malaria.
The South African variant includes 668 viruses reported from 26 countries, with local transmission mainly in southern Africa and the UK. These viruses carry nine non-silent mutations, six in the Spike protein.
The Brazil variant includes 30 viruses from eight countries, transmitting locally only in Brazil. These viruses carry 16 non-silent mutations, 11 in the Spike protein.
Three key RBD mutations — K417N/T, E484K, and N501Y — are found in variants that emerged in South Africa and Brazil. The UK variant has the N501Y mutation, but has another called P681H outside the RBD, which too increases infectivity.
How are vaccines tested for effectiveness against emerging variants?
Indirect tests are done in laboratories to assess if an emerging variant might escape antibodies developed after a natural infection or vaccination.
Serum (the blood components that contain antibodies) from recovered patients or vaccinated people, and antibodies known to neutralise the original virus, are tested to determine whether the variant viruses evade antibodies. Serial dilutions of the serum or antibodies are separately mixed with a fixed amount of the original and variant viruses, and the mixture is added to cells in culture. After a period of incubation, cells are washed and stained. Cells infected and killed by viruses multiplying within them appear as clear zones (plaques) on a dark background.
The effectiveness of a serum or antibody is expressed as an inhibitory concentration (IC) or plaque reduction neutralisation titer (PRNT) value. The IC50 or PRNT50 value is the reciprocal dilution of serum or antibody that neutralises 50 per cent viruses in the sample.
Since infectious viruses require containment facilities (called biosafety level 3; BSL3), these assays are sometimes done with pseudoviruses. These are constructed to carry the SARS-CoV-2 Spike protein on another virus background, and contain reporters that are easily visualised (e.g., green fluorescent protein) or quantified (e.g., luciferase).
Are the emerging variants susceptible to vaccines?
A number of lab studies published over the past week suggest that some SARS-CoV-2 variants evade antibodies triggered by vaccines and natural infection. An international team, which includes researchers from the African Health Research Institute and the University of KwaZulu-Natal in Durban, tested six people who had recovered from Covid-19 before the emergence of the new variant in South Africa. Convalescent antibodies in these people were six to 200 times less effective in neutralising the variant virus.
In a separate study posted on bioRxiv on January 19, researchers at the South African National Institute for Communicable Diseases in Johannesburg used pseudoviruses to show that South African variants completely escaped neutralisation by therapeutic antibodies. In further tests, the South African variant was fully resistant to serum from 21 of 44 recovered Covid-19 patients.
There is also proof of several re-infections with this variant in South Africa, driven by the ability of new variants to evade immunity developed against the original virus.
In a January 19 bioRxiv preprint, researchers from Pfizer and BioNTech show the serum from 16 volunteers taking their vaccine to equally neutralise the Wuhan virus and the UK variant.
Researchers from the University of Cambridge reported on January 20 that while serum from people given the Pfizer/BNT vaccine effectively neutralised pseudoviruses carrying the N501Y Spike mutation, 10 of the 15 vaccinees showed reduced neutralisation of pseudoviruses carrying the full set of Spike mutations from the UK variant.
Researchers at Rockefeller University in New York also reported in bioRxiv on January 19 on antibodies and memory in 20 volunteers given the Moderna or Pfizer/BNT mRNA vaccines. They found both vaccines to elicit similar responses, which were reduced by a “small but significant margin” against variants carrying the E484K, N501Y, or K417N:E484K:N501Y combination of mutants. They further found each of the mutations to abolish or reduce neutralisation to 14 of 17 potent monoclonal antibodies.
Interestingly, wild type viruses grown in the presence of vaccine-elicited antibodies gave rise to the same mutations, driving home the point that variant viruses evolved following immune selection in patients recovering from infection.
In a paper in the journal Science on January 25, researchers at the University of Washington, Seattle, mapped RBD mutations that affect binding to therapeutic antibodies used to treat Covid-19 patients. Their work shows how the Spike RBD can evolve in a persistently infected patient to evade antibodies, and that mutations escaping the antibodies are already present in SARS-CoV-2 strains in circulation.
The consensus from these recent laboratory studies is that emerging variants, especially the one from South Africa, could pose a challenge to current vaccines. There is no information yet for the Brazil variant that shares some of the same changes. However, these studies have only tested antibody responses, whereas vaccines also raise cellular immunity to eliminate infection.
Can new vaccines be developed to fight variants?
The evidence at this time, though of concern, does not indicate that current vaccines are failing. But this has to be watched carefully, and all efforts made to limit transmission between people, which drives mutations and the emergence of variants. Both Moderna and Pfizer/BioNTech have agreed that their vaccines offered reduced protection against the South African variant. The two companies are reported to be working on developing fresh vaccines to cover these variants. (The New York Times, January 25)
Should new vaccines be needed, the mRNA platform offers the best chance of speedy development. These vaccines were the first to receive emergency use approval, and have already been administered to millions of people globally. Would regulators require fresh human clinical trials for each variant vaccine built on an already approved platform? This would be critical to the speed at which vaccines against emerging variants can be deployed.
What should India do in this situation?
Only the UK variant viruses have so far been reported from India — and that too, in travellers. There is no reported local transmission, but considering its increased infectivity, this is likely to happen. The evidence so far suggests that current vaccines would still protect against the UK variant, even if with reduced efficacy.
In a January 26 preprint on bioRxiv, scientists from ICMR-National Institute of Virology and Bharat Biotech tested serum from 38 recipients of their vaccine, Covaxin, against a UK variant. The results show no significant difference, suggesting that the vaccine would work equally well on the UK variant. (Report, right)
With cases already going down, India should strictly implement masks and limit crowds while aggressively tracing contacts of people infected with the UK variant. The US has put a ban on travel from South Africa and Brazil. India must also be vigilant of people with a history of travel to South Africa since October 2020, and Brazil since December 2020.
Finally, the only way to catch emerging variants — whether imported or homegrown — is increased genomic surveillance. So far, there are only about 5,000 SARS-CoV-2 sequences from India in public databases, which accounts for merely 0.05 per cent of confirmed cases. The setting up of an inter-ministerial group — Indian SARS-CoV-2 Genomics Consortium (INSACOG) — to increase genomic surveillance is a step in the right direction.
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